US6300503B1 - Hydantoin intermediates for the synthesis of omapatrilat and methods for producing and using the same - Google Patents
Hydantoin intermediates for the synthesis of omapatrilat and methods for producing and using the same Download PDFInfo
- Publication number
- US6300503B1 US6300503B1 US09/589,571 US58957100A US6300503B1 US 6300503 B1 US6300503 B1 US 6300503B1 US 58957100 A US58957100 A US 58957100A US 6300503 B1 US6300503 B1 US 6300503B1
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- US
- United States
- Prior art keywords
- compound
- formula
- alkyl group
- group
- independently selected
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 *CCCC(C(N1*)=O)NC1=O Chemical compound *CCCC(C(N1*)=O)NC1=O 0.000 description 6
- UOTLHIOFZADJIR-UHFFFAOYSA-N C.CC(C)(C)C1OC(C)(C)C(C)(C)O1.COC(OC)C(C)(C)C Chemical compound C.CC(C)(C)C1OC(C)(C)C(C)(C)O1.COC(OC)C(C)(C)C UOTLHIOFZADJIR-UHFFFAOYSA-N 0.000 description 6
- RDDGNRSMTCJSAJ-UHFFFAOYSA-N CN1C(=O)NC(CCCC(C)(C)C)C1=O Chemical compound CN1C(=O)NC(CCCC(C)(C)C)C1=O RDDGNRSMTCJSAJ-UHFFFAOYSA-N 0.000 description 5
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N [H]C(=O)CCCC Chemical compound [H]C(=O)CCCC HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 4
- UCVWABKLWAEDFL-UHFFFAOYSA-N CCCCC(N)C(=O)O.[V] Chemical compound CCCCC(N)C(=O)O.[V] UCVWABKLWAEDFL-UHFFFAOYSA-N 0.000 description 3
- SREPHWQBZMYCIY-UHFFFAOYSA-N CCCCC1NC(=O)N(C)C1=O Chemical compound CCCCC1NC(=O)N(C)C1=O SREPHWQBZMYCIY-UHFFFAOYSA-N 0.000 description 3
- ULBIXENSCUEOFC-UHFFFAOYSA-N *.O=C1NC(=O)C(CCCC2OCCO2)N1 Chemical compound *.O=C1NC(=O)C(CCCC2OCCO2)N1 ULBIXENSCUEOFC-UHFFFAOYSA-N 0.000 description 2
- RMWKHZVRPMEDQS-UHFFFAOYSA-N CC(C)(C)C1OC(C)(C)C(C)(C)O1 Chemical compound CC(C)(C)C1OC(C)(C)C(C)(C)O1 RMWKHZVRPMEDQS-UHFFFAOYSA-N 0.000 description 2
- HWVFVLJLOVABPN-UHFFFAOYSA-I CC(C)(C)C1OC(C)(C)C(C)(C)O1.COC(OC)C(C)(C)C.I[V](I)I.I[V]I Chemical compound CC(C)(C)C1OC(C)(C)C(C)(C)O1.COC(OC)C(C)(C)C.I[V](I)I.I[V]I HWVFVLJLOVABPN-UHFFFAOYSA-I 0.000 description 2
- KABYGZMIZBLWGL-UHFFFAOYSA-N CCCCC(C#N)NC(C#N)CCCC Chemical compound CCCCC(C#N)NC(C#N)CCCC KABYGZMIZBLWGL-UHFFFAOYSA-N 0.000 description 2
- VQYCXZSHTSKOJO-BIGQKXQUSA-M CCCCC(C#N)NC(C#N)CCCC.CCCCC(N)C(=O)O.CCCCC1NC(=O)N(C)C1=O.CCCC[C@H](N)C(=O)O.[H]C(=O)CCCC.[V]I Chemical compound CCCCC(C#N)NC(C#N)CCCC.CCCCC(N)C(=O)O.CCCCC1NC(=O)N(C)C1=O.CCCC[C@H](N)C(=O)O.[H]C(=O)CCCC.[V]I VQYCXZSHTSKOJO-BIGQKXQUSA-M 0.000 description 2
- XUBRLDMMLUFLRU-UHFFFAOYSA-N COC(OC)C(C)(C)C Chemical compound COC(OC)C(C)(C)C XUBRLDMMLUFLRU-UHFFFAOYSA-N 0.000 description 2
- LVRLSYPNFFBYCZ-VGWMRTNUSA-N [H][C@]12CCC[C@@H](C(=O)O)N1C(=O)[C@@H](NC(=O)[C@@H](S)CC1=CC=CC=C1)CCS2 Chemical compound [H][C@]12CCC[C@@H](C(=O)O)N1C(=O)[C@@H](NC(=O)[C@@H](S)CC1=CC=CC=C1)CCS2 LVRLSYPNFFBYCZ-VGWMRTNUSA-N 0.000 description 2
- VUYNKKSEDYFYHT-UHFFFAOYSA-N C.CC(C)(C)C1OC(C)(C)C(C)(C)O1 Chemical compound C.CC(C)(C)C1OC(C)(C)C(C)(C)O1 VUYNKKSEDYFYHT-UHFFFAOYSA-N 0.000 description 1
- OYBRKKSYSKPXLA-UHFFFAOYSA-N CC(C)(C)C(OC1(N)N)OC1(N)P Chemical compound CC(C)(C)C(OC1(N)N)OC1(N)P OYBRKKSYSKPXLA-UHFFFAOYSA-N 0.000 description 1
- SIFHIRCCHGUSMC-UHFFFAOYSA-M CCCCC(C#N)NC(C#N)CCCC.CCCCC1NC(=O)N(C)C1=O.[V]I Chemical compound CCCCC(C#N)NC(C#N)CCCC.CCCCC1NC(=O)N(C)C1=O.[V]I SIFHIRCCHGUSMC-UHFFFAOYSA-M 0.000 description 1
- QKBNHVZTYVCMME-UHFFFAOYSA-M CCCCC(C#N)NC(C#N)CCCC.O.[H]C(=O)CCCC.[V]I Chemical compound CCCCC(C#N)NC(C#N)CCCC.O.[H]C(=O)CCCC.[V]I QKBNHVZTYVCMME-UHFFFAOYSA-M 0.000 description 1
- OZBPRAUPHDMXOO-UHFFFAOYSA-M CCCCC(C#N)NC(C#N)CCCC.[V]I Chemical compound CCCCC(C#N)NC(C#N)CCCC.[V]I OZBPRAUPHDMXOO-UHFFFAOYSA-M 0.000 description 1
- OLNIVXZAGRWDPO-UHFFFAOYSA-N CCCCC(N)C(=O)O.CCCCC1NC(=O)N(C)C1=O.[V] Chemical compound CCCCC(N)C(=O)O.CCCCC1NC(=O)N(C)C1=O.[V] OLNIVXZAGRWDPO-UHFFFAOYSA-N 0.000 description 1
- OYPVDODSMMWWKY-UHFFFAOYSA-N CCCCC1NC(=O)N(C)C1=O.[H]C(=O)CCCC Chemical compound CCCCC1NC(=O)N(C)C1=O.[H]C(=O)CCCC OYPVDODSMMWWKY-UHFFFAOYSA-N 0.000 description 1
- ICTRRBZWAYNWQS-JEDNCBNOSA-N II.N[C@@H](CCCCO)C(=O)O Chemical compound II.N[C@@H](CCCCO)C(=O)O ICTRRBZWAYNWQS-JEDNCBNOSA-N 0.000 description 1
- OLUWXTFAPJJWPL-YFKPBYRVSA-N N[C@@H](CCCCO)C(O)=O Chemical compound N[C@@H](CCCCO)C(O)=O OLUWXTFAPJJWPL-YFKPBYRVSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/24—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from hydantoins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
- C07D233/78—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- Omapatrilat was developed at the Bristol-Myers Squibb Pharmaceutical Research Institute as the first of a new class of compounds capable of simultaneously inhibiting ACE and NEP and is currently undergoing large scale clinical trials as an anti-hypertensive. See Omapatrilat. Drugs R D 1999 Apr;1(4):350-1.
- the invention is directed to novel compounds of the formula:
- R 1 is —H, a C 1 -C 5 alkyl group or a benzyl group and R 2 is represented by one of the two following formulae:
- R 3 , R 4 , R 5 , and R 6 are independently selected from the group consisting of —H or a C 1 -C 5 alkyl group and R 7 and R 8 are independently selected from the group consisting of a C 1 -C 5 alkyl group.
- Hydantoin (III) is an intermediate in the manufacture of racemic mixture (V):
- the S-stereoisomer, isolated from the racemic mixture, may be used, in place of compound (II), to produce omapatrilat.
- the overall reaction sequence for production of racemic mixture (V) is:
- Method A refers to the production of the novel hydantoin (III) of the invention directly from the monoacetal (XI).
- Method B refers to the production of the hydantoin via the dicyano intermediate and “Method C” refers to the production of the dicyano intermediate from the monoacetal (XI).
- the novel hydantoin is employed to produce racemic mixture (V).
- the S-isomer, isolated from the racemic mixture, is used to produce omapatrilat.
- Production of the racemic from the novel hydantoin of the invention is referenced as “Method D.”
- the invention relates to novel hydantoin compounds of the formula (III):
- the invention further relates to a process of preparing a racemic mixture of formula (IV) from the hydantoin.
- the S-stereoisomer of the racemic mixture can be isolated and employed, as a substitute for formula (II), in the production of omapatrilat.
- the hydantoin of the invention may be produced directly from the monoacetal of formula (XI) as well as via the dinitrile intermediate of formula (IV).
- the overall reaction sequence to generate the racemic mixture of formula (V) may be summarized as follows:
- R 1 is —H, a C 1 -C 5 alkyl group or a benzyl group.
- R 1 is —H or a C 1 -C 3 alkyl group.
- R 2 is represented by either of the two following formulae,
- each of the R 2 groups may independently be selected from (VII) and (VIII).
- Compound (IV) can be used as a starting material for synthesis of hydantoin (III).
- Hydantoin (III) is used as an intermediate in the synthesis of compound (V):
- Compound (III) may be synthesized by either Method A or Method B.
- Method A is summarized below:
- Any alkali cyanide, such as LiCN, as well as any organic cyanohydrin, such as a C 1 -C 6 aliphatic cyanohydrin, may be used in place of NaCN in Method A.
- the reaction scheme for Method A presented above illustrates the use of a H 2 O/EtOH blend as reaction medium, though a pure aqueous reaction medium may be used.
- the alcohol which may be either methanol, ethanol, isopropyl alcohol, propyl alcohol, butyl alcohol or i-butyl alcohol, increases the solubility of the monoacetal of formula (I) in water.
- the weight ratio of water:C 1 -C 4 alcohol in the reaction medium is 1:1 or more.
- the weight ratio of monoacetal:cyanide compound is typically between 2:1.
- the weight ratio of cyanide:ammonium carbonate is generally 1:13; and the weight ratio of reaction medium:monoacetal is typically 28:1.
- the reaction mixture is heated above room temperature, (20° C.). In a more preferred embodiment, the reaction mixture is heated to about 50° C. to about 57° C. The reaction mixture is allowed to react for a time sufficient to effectuate the reaction, preferably more than 2 hrs and more preferably greater than 6 hrs and even more preferably greater than 12 hours. In a preferred embodiment, the reaction product is recovered by adjusting the system pH from about 6 to about 10, preferably about 7, at which time the reaction product forms a solid white powder. The reaction is conducted at ambient pressure. Method (A) may further generate a minor amount of compound (IV) as an intermediate chemical species.
- Suitable for use as the ammonium compound for Method C is ammonium chloride or any other inorganic ammonium compound, such as ammonium sulfate, or an organic containing ammonium compound.
- the cyano compound used in Method A may likewise be used in Method C.
- the weight ratio of ammonium compound:cyanide containing compound for Method C is generally about 1:1.
- the aqueous media in Method C may be substituted with a C 1 -C 4 alkanol as discussed above for Method A.
- the weight ratio of reaction medium to monoacetal is about 4:1 and the weight ratio of cyanide containing compound:reaction medium is about 1:12.5.
- the reaction mixture for Method C is heated above room temperature (20° C.), preferably from 50° C. to about 52° C. at ambient temperature.
- the reaction mixture is allowed to react for an adequate amount of time to produce the compound of formula (IV), preferably more than 10 minutes, more preferably greater than 1 hour, and most preferably 2 hours or more.
- the pH of the reaction mixture is typically maintained between about 6 to about 10.
- the product is recovered from the organic phase by crystallization from acetone/water, more preferably followed by washing with toluene.
- the dicyano compound of formula (IV) may then be converted to compound (III) as shown in Method (B):
- the use of a non-carbonate inorganic ammonium salt, such as ammonium chloride, or an organo amnmonium containing compound (versus ammonium carbonate), causes the formation of the dicyano compound (III).
- Conversion of the dicyano compound (IV) to the hydantoin (Ill) requires the additional step of reacting the intermediate compound (IV) with carbon dioxide or a carbon dioxide generating compound such as ammonium carbonate.
- the addition of an alkali or ammonium hydroxide is also used in order to assist in the formation of the carbon dioxide.
- the weight ratio of carbon dioxide or carbon dioxide generating compound:hydroxide is generally between 1:1.75 and the weight ratio of carbon dioxide or carbon dioxide generating compound:reaction medium is generally 1:7.5.
- the reaction media can be purely water or any a mixture of any of the C 1 -C 4 alcohols referenced above.
- the reaction mixture in Method B is allowed to proceed generally at room temperature and at ambient or above atmospheric pressure (up to about 60 psig) for 10 minutes or more, more preferably for 2 hours or more and even more preferably for at least 6 hours at a pH of between from about 6 to about 10.
- the solution is brought to a pH of 7.5.
- the base in the reaction mixture of Method D is an alkali hydroxide, preferably either sodium hydroxide or lithium hydroxide, and the acid is preferably acetic acid, dilute hydrochloric acid or sulfuric acid, most preferably acetic acid.
- the weight ratio of hydantoin to alkali hydroxide to reaction media is about 1:1:6.
- the reaction mixture (D) is heated above room temperature (20° C.) and in a more preferred embodiment is heated to 100° C. or higher, and in an even more preferred embodiment is heated to 150° C.
- the reaction mixture is allowed to react for an adequate amount of time to produce the desired racemic mixture. This adequate reaction time is preferably more than 10 minutes and more preferably greater than 1 hour and even more preferably greater than 2 hours.
- the pH increases to about 12 or higher.
- the reaction mixture (D) is brought to pH 7 with the acid.
- the weight ratio of base:acid in the reaction is generally about 1:1.4.
- Example 3 The procedure set forth in Example 3 is repeated. In place of glutaric dialdehyde monoethylene glycol acetal, about 30 g of glutaric dialdehyde monomethanol acetal is used. All other reaction conditions may remain the same.
- Ammonium hydroxide (211 g, 2.22 equivalents; 28-30% in water) was charged and the solution was reheated to 100° C.
- Gaseous carbon dioxide (133.2 g, slight exotherm) was fed to the reactor at such a rate as to maintain system pressure near 60-65 psig and the reaction temperature at 100° C. The system was held at 100° C. for four hours. Excess carbon dioxide was vented from the system. A portion of the water was boiled overhead to facilitate the removal of ammonia and to make room for the next step.
- Lithium hydroxide (226.4 g, 3.33 equivalents; 10% in water) was added after the water strip. The system was brought to 150° C. for four hours.
Abstract
Description
Claims (38)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/589,571 US6300503B1 (en) | 1999-12-17 | 2000-06-07 | Hydantoin intermediates for the synthesis of omapatrilat and methods for producing and using the same |
PCT/US2000/034030 WO2001044202A1 (en) | 1999-12-17 | 2000-12-15 | Hydantoin intermediates for the synthesis of omapatrilat and methods for producing and using the same |
AU21048/01A AU2104801A (en) | 1999-12-17 | 2000-12-15 | Hydantoin intermediates for the synthesis of omapatrilat and methods for producing and using the same |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17244099P | 1999-12-17 | 1999-12-17 | |
US17233599P | 1999-12-17 | 1999-12-17 | |
US09/589,571 US6300503B1 (en) | 1999-12-17 | 2000-06-07 | Hydantoin intermediates for the synthesis of omapatrilat and methods for producing and using the same |
Publications (1)
Publication Number | Publication Date |
---|---|
US6300503B1 true US6300503B1 (en) | 2001-10-09 |
Family
ID=27390124
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/589,571 Expired - Fee Related US6300503B1 (en) | 1999-12-17 | 2000-06-07 | Hydantoin intermediates for the synthesis of omapatrilat and methods for producing and using the same |
Country Status (3)
Country | Link |
---|---|
US (1) | US6300503B1 (en) |
AU (1) | AU2104801A (en) |
WO (1) | WO2001044202A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6620600B2 (en) | 2000-09-15 | 2003-09-16 | Bristol-Myers Squibb Co. | Enzymatic resolution of aryl and thio-substituted acids |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3424783A (en) | 1966-05-06 | 1969-01-28 | Grace W R & Co | Aminonitrile synthesis |
US3862203A (en) | 1967-12-18 | 1975-01-21 | Stauffer Chemical Co | Process of manufacturing nitrilotriacetonitrile |
US4039527A (en) | 1974-10-04 | 1977-08-02 | Wako Pure Chemical Industries, Ltd. | Unsymmetrical azonitriles |
US4315022A (en) * | 1979-05-23 | 1982-02-09 | Beecham Group Limited | Terminal amino prostaglandin analogues |
US4543215A (en) | 1982-11-15 | 1985-09-24 | Basf Aktiengesellschaft | α-iminodiacetonitriles and their preparation |
US5508272A (en) | 1993-06-15 | 1996-04-16 | Bristol-Myers Squibb Company | Compounds containing a fused bicycle ring and processes therefor |
US5663363A (en) * | 1996-11-21 | 1997-09-02 | American Home Products Corporation | 2-thioxo-imidazolidin-4-one derivatives |
US5691335A (en) * | 1994-07-29 | 1997-11-25 | Suntory Limited | Imidazolidine derivative and use thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3638425B2 (en) * | 1998-01-29 | 2005-04-13 | 第一化学薬品株式会社 | Process for producing optically active α-aminoadipic acid-γ-semialdehyde ethylene acetal |
-
2000
- 2000-06-07 US US09/589,571 patent/US6300503B1/en not_active Expired - Fee Related
- 2000-12-15 AU AU21048/01A patent/AU2104801A/en not_active Abandoned
- 2000-12-15 WO PCT/US2000/034030 patent/WO2001044202A1/en active Application Filing
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3424783A (en) | 1966-05-06 | 1969-01-28 | Grace W R & Co | Aminonitrile synthesis |
US3862203A (en) | 1967-12-18 | 1975-01-21 | Stauffer Chemical Co | Process of manufacturing nitrilotriacetonitrile |
US4039527A (en) | 1974-10-04 | 1977-08-02 | Wako Pure Chemical Industries, Ltd. | Unsymmetrical azonitriles |
US4315022A (en) * | 1979-05-23 | 1982-02-09 | Beecham Group Limited | Terminal amino prostaglandin analogues |
US4543215A (en) | 1982-11-15 | 1985-09-24 | Basf Aktiengesellschaft | α-iminodiacetonitriles and their preparation |
US5508272A (en) | 1993-06-15 | 1996-04-16 | Bristol-Myers Squibb Company | Compounds containing a fused bicycle ring and processes therefor |
US5691335A (en) * | 1994-07-29 | 1997-11-25 | Suntory Limited | Imidazolidine derivative and use thereof |
US5663363A (en) * | 1996-11-21 | 1997-09-02 | American Home Products Corporation | 2-thioxo-imidazolidin-4-one derivatives |
Non-Patent Citations (6)
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6620600B2 (en) | 2000-09-15 | 2003-09-16 | Bristol-Myers Squibb Co. | Enzymatic resolution of aryl and thio-substituted acids |
US20040072310A1 (en) * | 2000-09-15 | 2004-04-15 | Jingyang Zhu | Enzymatic resolution of aryl and thio-substituted acids |
US20040077061A1 (en) * | 2000-09-15 | 2004-04-22 | Jingyang Zhu | Enzymatic resolution of aryl and thio-substituted acids |
US7026143B2 (en) | 2000-09-15 | 2006-04-11 | Bristol-Myers Squibb Company | Enzymatic resolution of aryl and thio-substituted acids |
US7141694B2 (en) | 2000-09-15 | 2006-11-28 | Bristol-Myers Squibb Company | Enzymatic resolution of aryl and thio-substituted acids |
Also Published As
Publication number | Publication date |
---|---|
AU2104801A (en) | 2001-06-25 |
WO2001044202A1 (en) | 2001-06-21 |
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